Accumulating evidence indicates that the failure to terminate a stress response in a timely manner, or the failure to adapt appropriately to repeated stress, can produce pathological changes suspected to play a role in the etiology of a number of mood disorders including anxiety and depression. This proposal is based on the idea that a better understanding of the brain areas and mechanisms responsible for habituation to psychological stress might help to identify targets putatively involved in the dysregulation of brain circuits associated with some forms of affective disorders. The proposed studies employ an animal model of chronic intermittent psychological (audiogenic) stress, utilizing a paradigm in which rats habituate over time to the behavioral and endocrine indices of the stress. Initially, external parameters important in these habituation processes will be established, such as the relevance of contextual cues. Secondly, the importance of the stress-induced increase in glucocorticoids in the habituation process will be determined using adrenalectomized rats with basal levels of corticosterone replaced. The third series of studies is designed to determine the specific brain areas involved in the habituation of the endocrine and behavioral responses to psychological stress. Brain areas known to be critical in the acute response to audiogenic stress, namely the paraventricular nucleus of the hypothalamus will initially be targeted. This area will be inactivated temporarily with intranuclear injections of lidocaine during habituation training, but will be active on the test day. A final study to determine the role of the orbitofrontal cortex in habituation to audiogenic stress is planned, using chemical lesions of the area prior to habituation training. This nucleus is targeted because preliminary data suggested that the neuronal activity in this area increases following habituation to audiogenic stress. Throughout these experiments, indices of habituation to stress will be monitored, including observation of behavior and analysis of the plasma stress hormones adrenocorticotropin hormone and corticosterone.